ToxSci Advance Access originally published online on June 27, 2003
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Toxicological Sciences 75, 117-123 (2003)
Copyright © 2003 by the Society of Toxicology
NEUROTOXICOLOGY |
Acrylonitrile Produces Transient Cochlear Function Loss and Potentiates Permanent Noise-Induced Hearing Loss
* Oklahoma Center for Toxicology, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73190; and
Hearing Research Laboratories, University Medical Center, Utrecht, The Netherlands
There is growing evidence that agents that produce oxidative stress in the cochlea have significant ototoxic potential by themselves and can potentiate noise-induced hearing loss as well. Acrylonitrile (ACN) metabolism entails conjugation with glutathione, resulting in rapid and pronounced depletion of this important antioxidant in many organs including brain, liver, and kidney. ACN metabolism also results in cyanide (CN) formation through a secondary oxidative pathway. The results of two physiological experiments are reported here. First, the acute effects of ACN (50 mg/kg sc) on auditory sensitivity are assessed using a within subject study. In the second study, persistent effects of ACN alone (50 mg/kg, sc and 2 x 50 mg/kg, sc) and ACN in combination with noise exposure (8 h, 108 dB octave-band noise) are evaluated using threshold sensitivity as the dependent measure. Auditory threshold shift and absolute thresholds were determined using the compound action potential (CAP) amplitude. Acute ACN administration produces a loss in auditory threshold sensitivity that reached a maximum 10–20 min following sc injection. Auditory thresholds returned to control levels 75–100 min following exposure. In the study of permanent auditory threshold shifts, ACN plus noise increased auditory threshold impairment relative to rats receiving noise only when thresholds were assessed 3 weeks following exposure. ACN by itself did not produce permanent threshold impairment 3 weeks following administration. Assays were undertaken in separate groups of rats to track the elevation in blood CN and the depletion of total glutathione in cochlea, brain, and liver following ACN treatment. Systemic blood CN levels were not significantly elevated until 60–120 min following injection, and cochlear glutathione levels showed significant depletion as little as 15 min after injection and remained depressed for about 4 h. The results confirm the prediction that ACN is acutely ototoxic and can enhance noise-induced hearing loss.
Key Words: ototoxicity; acrylonitrile; oxidative stress; potentiation; noise; cyanide; glutathione depletion.